Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis.

Leber's congenital amaurosis (LCA, MIM 204,000), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digito-ocular sign of Franceschetti). Hypermetropia and keratoconus frequently develop in the course of the disease. The observation by Waardenburg of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.

Mutation theory of carcinogenesis in retinoblastoma.

To test Knudson's hypothesis that two successive mutations are involved in retinoblastoma, we studied the data on 899 cases. Some of the findings appeared to differ from those that might be expected if Knudson's hypothesis were correct. Certain criticisms of Knudson's methodology and model were suggested. Alternative explanations proposed were 1) the role of the sequence in which mutations occur, and 2) the possibility of three mutational events.

The differential symptomatology of errors of collagen metabolism: a tentative classification.

We address the confusion in the current classification of inherited disorders of collagen and the excessive extension of the concept of the Ehlers-Danlos "syndrome" that tends to cover many facts and conditions frequently without strong clinical connection. We propose to subdivide the collagen disorders into four main classes depending on whether skin, joints, bone, or blood vessels are mainly involved. The class with mainly skin involvement includes the different forms of cutis laxa, Ehlers-Danlos syndrome types I and II (autosomal dominant), types V and IX (X-linked recessive), type VI (autosomal recessive), and type VIII (autosomal dominant). The group with mainly articular involvement includes Larsen and related syndromes and other types with a more benign course. The conditions with mainly skeletal involvement include the different forms of osteogenesis imperfecta. The class with mainly blood vessel involvement includes disorders of type III collagen and the Marfan syndrome. This tentative classification proposes a logical clinical framework that will allow easier integration of molecular biology data.

[The genetics of collagen diseases]. / Génétique des maladies du collagène.

Heritable disorders of collagen include Ehler-Danlos syndromes (11 types are actually known), Larsen syndrome and osteogenesis imperfecta. Their clinical, genetic and biochemical features are reviewed. Marfan syndrome is closely related to heritable disorders of collagen.

[Genetic counseling in ornithine carbamoyltransferase deficiency]. / Contribution au conseil génétique dans le déficit en ornithine carbamyltransférase.

Ornithine transcarbamylase (OTC) deficiency is an inborn error of urea cycle metabolism, responsible for lethal hyperammonemia in males and for severe symptoms in at least 20% of heterozygous females. The authors provide here additional data on the informativity of the protein loading test (PLT) for the detection of heterozygotes. They show that the risk of being a carrier for the mother of an affected boy falls from 2/3 a priori to only 1/8 if her PLT is negative. The risk for the mother of heterozygote girl falls from 1/2 a priori to 1/16 if her PLT is negative.

[Fifty years of medical genetics. A tribute to Maurice Lamy on the hundredth anniversary of his birth]. / Un demi-siècle de génétique Médicale. un hommage à Maurice Lamy, pour le centième anniversaire de sa naissance.

Before 1960, no disease gene had been mapped to human chromosome apart from the sex-linked characters which are carried by the X chromosome. The first assignments were inferred from the results of somatic cells hydridization and concerned enzymatic deficiencies and protein defects. They were followed by the data gained from the cytogenetics studies of microrearrangements, either deletions or translocations. The family and linkage studies began to be successfully undertaken following the discovery of polymorphic probes. The breakthrough came out with the availability of highly polymorphic microsatellites scanning quite evenly, the major part of the genome. Currently, more than 1,000 clinical disorders are mapped and compiled in the database GID/GENATLAS. They concern all chapters and extend to characters which are usually sporadic, such as malignant tumours and congenital malformations. The mapping endeavour already had great impact on our understanding of fundamental life processes and unveiled the extent of genetic heterogeneity of diseases. Its major consequences concern prenatal diagnosis. The applications tend to extend towards presymptomatic diagnosis, and screening of carriers, two procedures still controversial, which request due consideration of their inherent risks and side effects and cannot be undertaken without the informed consent of patients. Predictive testing for the detection of liabilities is still a subject of lively debate. Although the spectacular advances of mapping and its implications open great hopes for the prevention and even cure of disease, care has to be taken to their limits and risks and, in their approach, full consideration must be given the respect if human person.

[Prenatal, neonatal and postnatal prevention in cystic fibrosis]. / La prévention anté-natale, néonatale et post-natale dans la mucoviscidose.

The efficiency of neonatal screening for CF could be improved by associating a molecular analysis to the immunoreactive trypsin test, on the same dried blood's sample. However the interest of such a screening for the patients benefit remains controversial. In most cases, antenatal diagnosis may be performed by a direct search of the mutation(s). However, the impact of antenatal diagnosis on CF's incidence will necessarily be limited if it can only be implemented after the birth of an affected child. Hence the interest of screening programs for the detection of healthy carriers. Carrier's detection does not raise any objection for the relatives of patients. It is still premature to recommend it to be undertaken in the general population.

[Phenylketonuria yesterday and today. Evaluation of the work of systematic neonatal screening]. / La phénylcétonurie hier et aujourd'hui. Bilan de l'action de dépistage néonatal systématique.

Phenylketonuria is due in the very great majority of cases to a deficiency in phenylalanine hydroxylase, an enzyme whose cofactor is biopterin. Prenatal screening consists in measuring the concentration of phenylalanine in a sample of dried blood taken after birth (levels are already raised by day 3). Screening, organized by the Association française pour le dépistage et la prévention des handicaps de l'enfant, is very thorough (cover greater than 99%). Treatment involves observance of dietary restriction for at least five years. Results are good. Questions concerning the useful duration of dietary treatment, the level of phenylalanine that should not be exceeded, and the future of girls with PKU remain controversial. When adult, such girls may give birth to retarded children if they do not resume dietary restriction before becoming pregnant. Now that problems of screening, its organization, and the management of diet have been solved, these questions are the new challenge that faces us.

[Cystic fibrosis: a gene at the end of the road]. / La mucoviscidose: un gène au bout de la route.

The authors first give an account of the work undertaken jointly by two Canadian and one American groups, which lead to the cloning and identification of the cystic fibrosis gene. To achieve this aim, it was necessary to clone a large region amounting to 500 kb, using chromosome walking and jumping. The gene was located from a cross-hybridization signal with two probes from the cloned region and bovine cDNA. The CF gene is made of 24 exons giving a messenger of 6,500 nucleotides and a protein of about 1,500 aminoacids. The protein structure has been deduced from its composition in aminoacids. However, the localization of the protein in the cell and its true function remain an open question. At the same time workers from those groups identified the prevalent mutation in CF. These outstanding achievements will help unravelling the physiopathology of the disease. They increase the possibilities of prevention, but it is fanciful to think that they can lead to its eradication.

Genatlas database, genes and development defects.

This article aims to illustrate the potentialities of the Genatlas database, taking, as an example, the developmental genes and their associated diseases in man. These genes belong to several categories intervening from the first stages of embryonic life. They operate at all steps of developmental cascades from extracellular signaling to activation of target genes. Quite a number of those genes have been identified in man, which are the orthologs of genes previously described in lower species. These genes are mapped and an increasing number are associated with developmental anomalies. These studies shed light on the mechanisms of congenital malformations. They disclose a large array of genetic and phenotypic heterogeneity and a high degree of complexity.

Mapping the eye diseases.

In this review the authors first give an overview of the general strategies of mapping which differ whether the biochemical (molecular) defect of the disease is known or not. The main problems besides mapping are concerned for the first category with the correlation between mutation and phenotype and for the second, with heterogeneity, genetic vs phenotypic. Finally, tables are displayed of eye diseases or diseases with eye involvement (metabolic or not) which have been currently mapped, as well as candidate genes actually or putatively involved in visual transduction.